Polyunsaturated fatty acids (PUFAs) are metabolized by CYP450 enzymes that function as monooxygenases mainly by catalyzing hydroxylation and epoxidation (see Ref 1). Arachidonic acid (ARA) is metabolized by the CYP450s to hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs). While all EET isomers are almost equally formed, 20-hydroxyeicosatetraenoic acid (20-HETE), a product by ω-hydroxylation, is major HETE regioisomer derived from ARA. These metabolites are important lipid mediators that play important roles in various diseases (see Ref. 2). Interestingly, EETs and HETEs often have opposing biological functions (see Ref 2).
Every CYP450 produces both EETs and HETEs. However, epoxygenases, such as CYP2C and CYP2J isoforms, produce mostly epoxides, and hydroxylases, such as CYP4A and CYP4F isoforms, produce mostly 20-HETE. The same CYP isoforms also metabolize ω-3-polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to the corresponding epoxy- and hydroxyl polyunsaturated fatty acids (see Ref 3). Recently, beneficial effects from dietary supplements of fish oil including prescription ω-3 fish oil have triggered interests in the biological functions of their metabolites (see Ref 4). For example, it is showed that epoxides of EPA and DHA can reduce pain perception (see Ref. 5), blood pressure (see Ref. 6), and angiogenesis (see Ref. 7). Herein, the present disclosures are concentrating on the biological role of ω-hydroxy polyunsaturated fatty acid metabolites.
Biological roles of 20-HETE have been well studied, and have been shown to have detrimental effects on several diseases such as hypertension (see Ref 8), cancer (see Ref. 9), and cardiovascular and kidney diseases (see Ref 10). In addition, there is growing evidence to suggest that 20-HETE is a potent agonist of the transient receptor potential vanilloid receptor 1 (TRPV1) which is activated by endogenous lipid mediators and is closely related to pain (see Ref. 11).
However, little is known about the biological roles of other ω-hydroxylated PUFAs due mostly to their limited availability or difficulty to synthesize them. These are 20-hydroxyeicosapentaenoic acid (20-HEPE) and 22-hydroxydocosahexaenoic acid (22-HDoHE) derived from EPA and DHA respectively. 22-hydroxydocosahexaenoic acid (22-HDoHE) is an endogenous lipid mediator produced by cytochrome P450 ω-hydroxylases (largely CYP4A and CYP4F) from docosahexaenoic acid (DHA, 22:6 ω-3), as shown in FIG. 1A. It is an endogenous compound and has been detected in many tissues such as brain, lung, kidney and liver, as shown in FIG. 1B (see Ref 35).
Gopal et. al. reported a chemical synthesis of 20-HETE by a Suzuki-Miyaura cross-coupling of a cis-vinylbromide compound with a functionalized borane (see In Tetrahedron Lett. 2004, 45 (12), 2563-2565). Apart from that, several biosynthesis of 20-HETE have been reported (see Ref 12). Harmon et. al. reported a 20-HEPE synthesis by oxygenation of ω-3 fatty acids by human cytochrome P450 4F3B (see Prostaglandins, leukotrienes, and essential fatty acids 2006, 75 (3), 169-77). However, a complete synthesis of 22-HDoHE has not been reported yet.
In view of the number of possible applications for the treatment of diseases there is a need for a synthetic chemical method of preparing 22-HDoHE, 20-HEPE, and 20-HETE.
Described herein, inter alia, are solutions to these and other problems in the art.